ABSTRACT Millions of workers in the US and worldwide, including professional welders, experience prolonged, high- dose occupational exposures to manganese (Mn). Over-exposure to environmental manganese (Mn) has long been established as a cause of adverse motor system effects that have clinical features similar to parkinsonism (PS), which is the most common clinical manifestation of Parkinson disease (PD). There is also evidence that Mn exposure can induce dysfunction of cognitive control, mood, and behavior. The primary goal of the proposed investigation is to perform a comprehensive clinical assessment of Mn-related motor and cognitive system neurotoxicity among a well-characterized cohort of professional welders we have studied for the past 13 years. Accordingly, we will extend our clinical assessments of motor system toxicity and conduct a comprehensive battery of cognitive and behavioral tests, and estimate dose-response relations with Mn exposure. The cognitive/behavioral battery will be a new feature of the study. We will also test the hypothesis that plasma proteins known to be associated with PD: alpha synuclein (SNCA), protein dyglycase (DJ1 [PARK7]), and ubiquitin carboxy-terminal esterase (UCHL1), are associated with risk, severity, and progression of PS in the cohort. The study will be conducted among 500 (of 938) welders who will be re-enrolled. The proposed study will be the most comprehensive clinical assessment of motor and cognitive neurologic outcomes in an Mn-exposed cohort conducted to date. An especially novel feature of the proposed study is characterization of protein biomarker measurements that may serve as preclinical indicators of subsequent clinically determined parkinsonian outcomes. The findings from this research should have important implications for setting occupational Mn exposure standards, and may ultimately inform disease prevention strategies for Mn-related adverse neurological outcomes.